Texas scientist may have key in cancer war

Jim Allison is chairman of immunology at the University of Texas M.D. Anderson Cancer Center.

Photo By For the Chronicle

Jim Allison, Ph.D., an M.D. Anderson researcher whose ground breaking research enabled doctors to enlist the immune system to fight cancer. For Sunday story on the new approach. With important "Breakthrough Prize in Life Sciences" in his lab at the McCombs Institute for the Early Detection and Treatment of Cancer, 7555 Fannin Street.
1/24/14 (Craig H. Hartley/For the Chronicle)

Photo By For the Chronicle

Jim Allison, Ph.D., an M.D. Anderson researcher whose ground breaking research enabled doctors to enlist the immune system to fight cancer. For Sunday story on the new approach. With important "Breakthrough Prize in Life Sciences" in his lab at the McCombs Institute for the Early Detection and Treatment of Cancer, 7555 Fannin Street.
1/24/14 (Craig H. Hartley/For the Chronicle)

Decked out in black tie, Jim Allison stood on the red carpet in Silicon Valley.

It was unfamiliar territory for the small-town boy from South Texas who had become a scientist and spent his research career on what many considered a lost cause: the study of the immune system's cancer-fighting potential.

But he always believed that's where the action would be, and now here was Facebook CEO Mark Zuckerberg saying Allison's breakthrough “will change lives for generations to come.”

For that, television host Conan O'Brien handed him the 2014 Breakthrough Prize in Life Sciences award, which includes a $3 million check.

Allison had become a rock star.

There had been something independent in him since high school, where he battled teachers over creationism.

There'd been an extraordinary run of cancer deaths in his family, including his 45-year-old mom, which convinced him there had to be better treatment than radiation and chemotherapy.

And there had been that wild, creative streak that once led to him blowing a harmonica with Willie Nelson.

Whatever the source of his genius, Allison, chairman of immunology at the University of Texas M.D. Anderson Cancer Center, is credited today with one of the most important breakthroughs in cancer history, the discovery that finally frees the immune system to attack tumors.

Allison did it — made the discovery, then translated it into a drug — in a climate that wasn't exactly welcoming.

The achievement has recently won Allison a raft of awards that M.D. Anderson President Dr. Ron DePinho thinks will culminate in the Nobel Prize.

“By creating this brilliant approach that treats the immune system rather than the tumor, Jim Allison opened a completely new avenue for treating cancers,” De-Pinho says.

The 65-year-old Allison insists he never set out to cure cancer. Rather, he describes his motivation as “the selfish desire to be the first person on the planet to know something.”

“It can be hard to go against the system,” Allison said, “but sometimes you have to do it for progress to be made.”

Six months before his red-carpet moment, Allison found himself arriving late to Chicago's Arie Crown Theater, site of an immunotherapy session at the American Society of Clinical Oncology's 49th annual meeting.

For years, he'd been going to such gatherings. Historically, they'd been sparsely attended, the result of a series of flops that changed the idea of enlisting the immune system to fight cancer from the field's Holy Grail to a forgotten stepchild.

But here were 4,000 doctors who'd come to hear how the immune system was saving the lives of patients whose cancers historically meant a death sentence. They had come because of a flash of brilliance by Allison that deciphered which molecules on the surface of T cells function as catalysts — and which one functions as the brake.

Early rebellion

Allison grew up in Alice, the son of a country doctor who'd hoped the boy would follow in his footsteps.

Young Allison he was advanced enough as a student to chafe at the idea of a science curriculum influenced by religious-minded teachers. Even then, he recalls, he knew evolution is to biology as Newton is to physics. How could a biology class omit its most basic tenet?

So Allison did what any future maverick scientist would do: He refused to take the class.

Ultimately, a compromise was reached that would allow Allison, then a senior, to satisfy the requirement by taking UT-Austin's freshman biology course by correspondence.

A rebel was born.

Descended from a long line of Texans and the youngest of three brothers, he was bookish, outdoorsy, an Eagle Scout and straight-A student who loved dissecting frogs.

He was 11 years old when his mother died. She'd been sick with lymphoma for some time, but he had no idea how seriously when his father called him to her bedside. She died as he held her hand.

The family cancers would keep coming. He lost an uncle to melanoma, another to lung cancer. Years later, his brother would die of prostate cancer, a cousin of ovarian cancer.

It was all a motivating force, he says, but emphasizes he never considered curing cancer his purpose.

“If I had, I'd never have found the immune system's brake,” says Allison, who was diagnosed with prostate cancer and successfully treated by prostatectomy in 2005.

“I always had in the back of my mind that if my research uncovered something that might help, I'd make the leap,” he says. “But I always knew the key was figuring out how things work, finding the right button to push.”

The hardest thing to accept was that his breakthrough didn't come soon enough to save his brother. Allison was at his brother's side, too, when he died.

At 16, Allison graduated from high school and went to UT, where he quickly lost interest in going on to medical school, soured by the realization that doctors have an inordinate amount of responsibility.

“As a scientist, you make mistakes all the time — that's how you learn,” says Allison. “But a physician has to be right all the time. I prefer the scientist's life — get an idea, devise an experiment, learn if it checks out. You only have to be right sometimes.”

After completing his undergraduate studies and Ph.D. at UT, Allison went to Scripps Clinic and Research Foundation near San Diego, Calif., for his postdoctoral fellowship.

Some of his most lasting memories there didn't involve science.

In harmony with Willie

For a couple of years, he played regularly with Clay Blaker and the Texas Honky Tonk Band. The stars aligned for his stint with Willie Nelson. He'd wangled an invitation to a party Nelson's label threw to celebrate the “Red Headed Stranger” album going platinum. When Nelson asked Allison if he knew anywhere he could pick some music the next night, Allison didn't hesitate to volunteer it was Talent Night at the Stingaree bar where he played.

Allison would join Nelson on stage there for “Blue Eyes Crying in the Rain.”

For all his love of music, Allison had no illusions. Asked by Blaker to accompany the band when it left southern California to play Texas clubs, Allison opted to keep his day job.

He returned to Texas a year after completing his Scripps Clinic fellowship. He showed up at M.D. Anderson's new science campus in Smithville, asked for employment and procured a biochemist job. He was the center's sixth hire.

By then, the mid-1970s, Allison already was keenly aware of cancer immunotherapy's checkered history.

It was all the rage for a time — some prominent scientists proposed in the '60s that one purpose of the immune system is to protect against cancer — but when early mice experiments didn't show benefits, immunotherapy fell out of favor.

In the ensuing years, cancer immunotherapy made some strides, but they frequently were undermined by hype, sometimes by the scientists themselves. Allison felt that none of them really knew what they were doing. He set out to be the one who did.

Allison had free rein at Smithville to study the immune system, then in its research infancy.

He'd become fascinated following an undergraduate experiment he conducted that showed mice cured of leukemia had acquired an immune response that rejected his attempts to inject new tumors.

He'd become even more interested as he learned of the immune system's complexity, the communication and coordination it calls upon to recognize and eliminate any pathogen, all without causing damage to healthy tissue.

Allison was most interested in T cells, the immune system's little-understood soldiers that “do all the killing.”

Allison wondered what about cancer disarms them. Why do they so efficiently attack virus-infected cells but not get the necessary signals to attack tumors?

In the next decade, Allison's work laid important groundwork. He identified, first, the T cells' ignition switch, a receptor that has to recognize proteins on tumor cells; then the gas pedal, a co-stimulatory molecule necessary to activate the T cells. They would provide key insights that helped facilitate the big discovery still to come.

In that time, the University of California at Berkeley came recruiting. It was no easy decision for Allison, who loved his laid-back life — weekends watching his favorite Texas music acts in Austin, weekdays able to hike and canoe on land he'd bought within walking distance of work.

He dithered for two years, but finally decided it was time to make the move. It took a former adviser telling him if he passed the job up, he'd put up his feet 10 years later thinking he could have been a contender.

The heavyweight bout would come sooner than expected.

Work in the 1990s

By the '90s, the race was on.

Numerous immunology labs were looking for molecular signals to rally T cells into action, and nothing looked so promising as CTLA-4.

A newly discovered protein that protrudes from T cells' surface, CTLA-4 turned out to resemble the structure of the “gas pedal” Allison described, so it seemed logical that it was an activation signal.

But when he tried binding molecules with CTLA-4 as he had done with the “gas pedal” protein, he got an opposite effect: It inhibited T-cell proliferation. Could it be a brake, not a gas pedal?

So while most everyone else was looking for evidence that CTLA-4 turned on the immune system, Allison designed a study based on the hypothesis that CTLA-4 turned it off.

He implanted mice with cancer cells and treated some with an antibody that blocked CTLA-4 — in essence, taking the brake off the immune system.

Allison was astounded by the initial data his research fellow showed him at the end of November 1995: While all the untreated mice had died, 90 percent of the cancers of the treated mice had disappeared.

Allison wanted to reproduce the results immediately, but his fellow was headed off to a European vacation, and Berkeley would soon be closing for Christmas.

Allison instructed the fellow to inject tumors into a new bunch of mice, including a control group that didn't get the antibody. He'd come in during the break and monitor the mice himself, unaware which was the control group and which got the treatment — a truly blinded study.

Allison took the measurements every other day during December and, for a short while, the results were the source of despair. All the tumors were continuing to grow. But at about the third week, things began to change. In half of the mice, the cancers first stopped growing, then started shrinking, then disappeared.

He developed an antibody that worked great in mice, but for two years couldn't find a company to fashion a human version.

Finally, the New Jersey company Medarex took the plunge, sublicensing the patent and manufacturing a drug called ipilimumab (ippy for short), the first of a new class of drugs called immune checkpoint inhibitors.

The company ultimately would be acquired by Bristol-Myers Squibb for $2.4 billion.

Ippy was tested, successfully, in human patients for the first time in 2001, but results from its first large-scale trial weren't good. There was little impact at 12 weeks, the point at which chemotherapy is assessed, so it was declared a failure.

It took a second large trial for ippy's prospects to gain momentum, after clinicians noticed some tumors that were unaffected at 12 weeks had shrunk; years later, some patients were thriving.

It turns out the immune system sometimes took time to rev up, but once it did, its effects last, unlike other cancer therapies.

Tearful reunion

Sharon Belvin burst into tears in September 2006 when she was introduced to Allison.

Now employed at New York's Memorial Sloan Kettering Cancer Center — he'd left Berkeley in 2004 so he could work closely with doctors and make sure his discovery wasn't mishandled — Allison had stopped by the office of Dr. Jedd Wolchok, his clinical partner. There was Belvin, the first patient he'd ever met who had received his drug.

She'd been diagnosed, at 22, with Stage 4 melanoma, words she says are “impossible to hear and not think 'death.” In the next year, when nothing stopped the spread of Belvin's cancer from her chest and lungs to her brain, Wolchok offered her ippy. Desperate, she jumped at the chance.

Infused through a vein every three weeks over three months, ippy quickly shrank Belvin's tumors and had her walking again. A year later, the day Wolchok summoned Allison, she'd just gotten the news that she was in remission.

It wasn't just Belvin who got teary-eyed. Her husband and Allison choked up, too. After a moment, all embraced in a group hug.

“That's the reason you do this work,” says Allison. “It's not about the awards, it's about the difference made in people's lives.”

Eight years later, Belvin, 32, and Allison remain in touch, typically bumping into each other once or twice a year at cancer advocacy functions.

“What can I say?” Belvin says. “He gave me back a life.”

It would take 10 years of trials involving 6,500 patients, but in 2011 the Food and Drug Administration finally approved ippy — brand name Yervoy — for skin melanoma.

No previous treatment ever made a meaningful dent in the advanced disease's five-year death rate of more than 95 percent, but the latest statistics show nearly a quarter of all melanoma patients treated with ippy live at least three years, after which point none die of the disease.

Back to Texas

For a time, Allison loved living on Manhattan's Upper East Side, but the charm eventually wore off.

“I'm not a New Yorker,” he says.

Dr. John Mendelsohn, then president of M.D. Anderson, began wooing him to Houston, promising the hospital could provide an even larger platform for Allison's work.

When Mendelsohn retired in 2011 without making a formal offer and was replaced by DePinho, Allison wondered whether the moment had passed. He remembered how DePinho, a decade earlier, goaded him during a taxi ride to a meeting in Italy that immunotherapy never would work.

But even before taking office, DePinho pushed hard to pick up the recruitment, telling Alison it was imperative to engage the immune system to beat cancer, making immunotherapy a linchpin of M.D. Anderson's “Moon Shots” initiative to cure some of the most deadly tumors.

Allison accepted in late 2012,a year after the Cancer Prevention and Research Institute of Texas approved a $10 million grant for his recruitment.

M.D. Anderson invested $30 million more to bolster its immunotherapy research capabilities, which enables Allison to design trials across a variety of tumor types, using ippy by itself or combining it — with other checkpoint inhibitors and with chemotherapy or targeted therapy.

It also provides Allison access to freshly removed tumors, which he can analyze to gauge ippy's effect and understand how it works, as he did with mice.

Allison says he has no plans to retire.

Allison enjoys the good life. He tools around in a Porsche convertible, whose vanity license plate bears the characters CTLA4. He says he might buy a sailboat.

But in other ways, he remains a child of the '60s. He once suggested the FDA place an “h” at the front of “ippy.” The shaggy-haired harmonica player still surfaces regularly, only now he plays with a band made up of other M.D. Anderson doctors.

Busy schedule

Allison is wildly in demand on the lecture circuit, traveling constantly to evangelize about cancer immunotherapy's promise.

The speaking engagements come not just because of Allison's drug but because his discovery blasted open the door for cancer immunotherapy.

Scientists since have discovered eight other immune system brakes and developed a few corresponding pharmaceuticals now in clinical trials. One of them, combined with Yervoy in the trial presented at the ASCO meeting, brought advanced melanoma patients' 11/2-year survival rate to 80 percent. The National Institutes of Health in 2011 began funding a network of 27 centers' immunotherapy trials. Every major pharmaceutical company is investing heavily.

Because the target is the immune system rather than the tumor, immune checkpoint drugs are expected to work on all sorts of cancers. Besides melanoma, Allison's drug and the others in clinical trials already have had success against cancers of the lungs, colon, kidney, breasts, ovaries, pancreas and prostate.

“There's a sense of paradigms shifting,” Science magazine wrote in an article that declared cancer immunotherapy the Breakthrough of the Year for 2013. “Immunotherapy marks an entirely different way of treating cancer — by targeting the immune system, not the tumor itself. Oncologists, a grounded-in-reality bunch, say a corner has been turned and we won't be going back.”

For all the excitement, there still are questions about ippy. Researchers have no idea why it benefits some people but not others. Because releasing the brake facilitates an all-out attack by the immune system, it can cause serious side effects — colitis, skin rashes, impaired pituitary function — that must be managed.

And the drug's price is $130,000, an amount Allison calls obscene.

Still, years of skepticism about immunotherapy finally have faded. Allison notes that even James Watson, Nobel Prize-winning co-discoverer of DNA's structure and onetime immunotherapy skeptic, recently told him, “This is going to do it.”